Project Summary/Abstract The long-term goals of these studies are to establish and apply emerging optical neuroimaging methods, namely diffuse optical tomography (DOT), to map brain function in school-aged children with Autism Spectrum Disorder (ASD) during direct within-room social communication. DOT has the potential to elucidate underlying mechanisms, inform clinical interventions, and improve outcome of ASD, thus these aims are in direct correspondence with the mission of NIMH: to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. ASD, defined by deficits in social communication and restricted interests/repetitive behaviors, is a serious psychiatric disorder of childhood, is treatable but currently incurable, and affects an estimated 1 in 68 children in the United States at an estimated annual cost of $268B.Early behavioral and educational interventions, starting at 18-24 months of age, improve outcomes in a subset of patients. Recent advances in functional brain imaging show promise that signatures of brain function may provide reliable markers of ASD severity and may be sensitive to interventional therapy. However, current neuroimaging methods (e.g. functional magnetic resonance imaging, fMRI) are not ideal in research on cognitive-behavioral domains affected in ASD; the loud and constraining MRI environment limits studies on direct within-room social communication involving auditory processing and language generation and presents an excessively challenging setting for sensitive participants, such as school-aged and in particular young children or those severely affected with ASD. DOT provides a compelling alternative that overcomes the significant ergonomic limitations of fMRI and silently images brain function with a wearable cap. However, DOT has yet to be established in studies involving direct within-room social communication. To progress DOT towards this goal, simple language paradigms, validated in healthy adults against subject-matched fMRI, will be adapted for within-room dyadic studies. This project will follow a systematic progression away from the computer interface, standard in neuroimaging, towards a direct natural socio-communicative paradigm, and will lay the foundation for follow-up studies of early childhood development. Aim 1 will use established paradigms of hierarchical language processing for within-subject validation of DOT-based neuroimaging in school-aged children with ASD and sex-, age-, and IQ- matched typically developing controls against fMRI. In Aim 2, a within- room participant will present language and social-communication paradigms. These studies are innovative and significant because the comfortable scanning environment of DOT will enable brain imaging of ASD throughout an extended spectrum of patients, and will lay the groundwork for DOT neuroimaging studies on infants and toddlers at high risk for ASD. This will facilitate longitudinal studies that will map the developmental trajectory of ASD, using paradigms that may combine neuroimaging with behavioral assessment, from infancy to adulthood, and track the effects of interventions with neurophysiological metrics and behavior.